I can’t resist mentioning that today I caught part of another old baseball flick in the gym. Pride of the Yankees, on TCM, features Gary Cooper as Lou Gehrig. Sam Wood directed this 1942 MGM classic in which Babe Ruth appears, briefly in cameo, as Babe Ruth. A Times reviewer, writing after its July 1942 release, complained that the film didn’t include enough baseball, nor sufficient drama until its end. That may be true. But your athletically-challenged author was moved by this film, and stopped by some of the scenes depicting how information was conveyed in that era, about the star’s declining health.

movie poster, 1942 film “Pride of the Yankees”

I learned about Lou Gehrig in medical school. Amyotrophic Lateral Sclerosis (ALS, aka Lou Gehrig’s Disease) is a progressive and serious neurological disease that tends to affect a person’s voluntary (“motor”) muscles, such as those of the arms, legs and face. The CDC maintains a national registry for the condition, which is of unknown cause and, to the best of my knowledge today, remains on the shortening list of incurable conditions. The NIH estimates that 20-30,000 people are living with ALS, and that some 5,000 or so are found to have this condition each year in the United States. It typically affects, or “strikes” – as it’s almost universally metaphored, people in their forties or fifties.

A former colleague, whom I admire and will always remember for what he has taught me about immunology and even more by his working through illness, has ALS and has continued contributing for the long time, over 20 years, that I have known him. What enables some people with illness, i.e. patients, to keep contributing in their field of expertise is, first, their wanting to keep working. But it also requires a sensitive and encouraging environment – a workplace that allows people with knowledge, who become disabled or limited by health concerns, to work as best they can.

I learned that Lou Gehrig was a New Yorker. He was born to German immigrants in Yorkville, near where I live in Manhattan. According to his biography in the Baseball Hall of Fame, the left-hander was born in June 19, 1903 and died on June 2, 1941, a few weeks shy of what would have been his 38th birthday. He was called the Iron Horse and played first base for the Yankees. In the movie, it takes Gehrig a while to realize, or admit, that he can’t play baseball – that he’s stumbling and struggling to even hold a bat, or run or walk. Once the athlete acknowledges his limitations, he is treated kindly and generously by his manager, teammates and fans. At first, the doctor in the Scripps Clinic doesn’t want to tell him the truth about his condition. But Gehrig wants the numbers, the statistics, facts. Finally, after Cooper, playing Gehrig, asks him if it’s “three strikes.” The doctor answers that, yes it is. The patient understands his meaning. No one in the room can pronounce the words “amyotrophic lateral sclerosis,” but Gehrig gets the picture. The patient doesn’t want to tell his wife but, as these things usually go, she figures it out.

The Yankees and Gehrig’s manager try to keep his illness a secret, but after he gives up his spot on the roster, it becomes progressively evident that something is seriously wrong. One nugget in the film is an interaction with what might be considered a peer patient. Early on, Gehrig encounters a boy who can’t walk, and offers him encouragement. Later, once Gehrig’s condition has become evident, the young man comes to tell him thanks, and to show Gehrig he’s gotten better, by not giving up. But the boy becomes tearful and appears not to enter the stadium. It seems his hero’s deteriorating condition is too much to watch.

On July 4, 1939, Gehrig gave a speech before a packed Yankee stadium. He thanked his teammates, coach, sportscasters, athletes of other teams, fans, his parents and his wife, and concluded, famously, that he was “the luckiest man on the face of the Earth.”

Today’s Annals of Internal Medicine includes new results for the CLOTS (Clots in Legs Or sTockings after Stroke) Trial. Not-quite acronyms aside, it’s an interesting study with implications for many patients at risk for deep venous thrombosis (DVT).

compression stockings - NIH image (Medline Plus)

This U.K.-based study, involving 3114 patients in 112 hospitals in 9 countries, used ultrasound to evaluate possible DVTs in legs of people after they’d been immobilized upon suffering strokes. Patients were randomized to receive either thigh-length or below-the-knee compression stockings while recovering in the hospital. The main result was that 98 of 1552 (6.3 %) of patients who received thigh-length stocking and 138 of 1562 (8.8%) of patients with below-the-knee stockings developed DVT. This difference is highly significant (p = 0.008).

The twist is this: in a separate, extensive recent Cochrane review the investigators compiled data from multiple randomized studies of stockings in stroke patients and established that thigh-length stockings were inferior to no stockings, i.e. stroke patients who wore thigh-high compression stockings were more likely to develop DVTs than those who didn’t wear any stockings at all. The authors reconcile these separate results by suggesting that below-knee stockings might increase the risk for DVT after stroke.

Confusing? Yes. The bottom line is that thigh-high compression stockings may not help, based on the Cochrane analysis; below-the knee stockings may hurt.

Why this matters is that the results have implications for other hospitalized patients at risk for DVT, like people who’ve had hip replacements, pelvic or spine surgery. “Unfortunately, no randomized trials have compared below-knee stockings with no stockings,” the authors write.

An accompanying editorial in the Annals considers the “puzzling” findings of the CLOTS trials and addresses how clinicians might prevent DVT in patients with stroke:

…The unexpected findings that thigh-length stockings are not very effective at preventing venous thromboembolism and that below-knee stockings might increase incidence of thrombosis in patients with stroke should prompt a reevaluation of the role of graduated compression stockings in other groups of patients….Clinicians need to realize that despite the ubiquity of graduated compression stockings in many settings, the net benefits and risks of this seemingly innocuous intervention remain uncertain.

As a hematologist, I see this as a low-tech, big deal because DVTs are a huge source of morbidity and mortality.

In the U.S., the number of clots per year runs in the hundreds of thousands. DVTs tend to arise in people who are immobilized after surgery, with neurological impairment and during travel. The elderly are particularly susceptible, as are pregnant women and people with inherited clotting dispositions. The National Blood Clot Alliance provides an interactive map of the incidence of DVTs, state by state, on its website.

Personally, I love it when the doctors allow me to take off the boots when I wake up after a procedure, so I can kick my feet around and, I hope, reduce my risk of DVT by movement and exercise. Compression stockings feel like corsets on my calves; they’re warm and constraining. On planes, too; I find stockings restrictive.

My own experience aside – the data supporting the use of compression stockings are limited, and this new study suggests they can be damaging.

Last week, doctors injected embryonic stem cells into a human patient with an acute spinal cord injury. The procedure took place at Shepherd Center, a hospital and research center for spinal cord and brain injury in Atlanta, GA. The patient was the first to receive human stem cells derived from an embryo in an FDA-approved research protocol in the U.S.

The phase I trial, sponsored by Geron Corporation of Menlo Park, CA, is primarily intended to evaluate the treatment’s safety. The company has developed a way to culture and purify oligodendrocyte progenitor cells (OPCs – primitive neuronal cells) from human embryonic stem cells (h-ESCs). These precursor cells, obtained from human embryonic tissue, can be coaxed, at least in vitro, to develop into one of various mature cell types, including neurons).

So what defines stem cells?

Stem cells are considered pluripotent, meaning that they have the capacity to differentiate, or mature, into specialized, distinct cell forms depending on nearby cells and stimulatory molecules in their environment. Mature cells, by contrast, have already “decided” what kind of tissue they’ll grow into – whether that’s part of the eye, or the heart, liver tissue, nervous system or any other body component.

The idea behind stem cell therapy for spinal cord injury is to provide the wounded spine with fresh, primitive cells that might grow into neurons and replace those that have been damaged. The protocol is highly-experimental.

Today while on a train I caught up on some reading, including the August 30 issue of the New Yorker. I learned about prosopagnosia – the inability to recognize faces and some aspects of place/orientation.

The information came through a typically curious article by Dr. Oliver Sacks, a neurologist, author – of The Man Who Mistook His Wife for a Hat fame – and New Yorker, whom I met briefly one day in a class at Columbia University. Unabashedly, Sacks details his own mishaps in recognizing people he’s met and finding his way; it’s a life-long, inherited affliction that requires he remember individuals by things other than how they look. Half-generously, the magazine provides non-subscribers a detailed abstract of Face Blind that’s far less charming than the original piece but relatively rich in the medical details:

Severe congenital prosopagnosia is estimated to affect two to two and a half per cent of the population—six to eight million people in the United States alone.

What makes this question so ripe, in my oncologist-patient-teacher-blogger’s way of thinking, is that we may never, even if formal studies do provide data on this issue 10 years ahead, reach an objective conclusion on this matter.

The problem is this: To prove that empowered patients are “better and healthier,” how would we design a trial? If we were to compare those engaged – who almost by definition are more educated or at least have Internet access, or who are one way or another are linked to people who can help them find needed information – they’d likely do better than the disconnected patients. But the outcome might be a function of confounding variables: their education, economic status, on-line connectivity, etc.

I think the answer is inherent in the goal of being engaged, and this has to do with the concept of patient autonomy – what’s essentially the capacity of a person to live and make decisions according to one’s own set of knowledge, goals and values.

Autonomy in medicine, which borders on the empowerment idea, can be an aim in itself, and therefore valuable regardless of any measured outcome. For autonomy, or patient empowerment, to be meaningful and maybe even “better” in the strictly medical sense, as measured by outcomes like survival or quality of life, there needs be stronger public education in the U.S. and everywhere.

You can read all you want on stem cells, gene therapy or rare forms of chronic leukemia that are driven by a turned-on oncogene, but if you don’t know the basics of science and math, or don’t have sufficient language skills to read and absorb new knowledge or at least ask pertinent questions, it’s easy to get lost in that information, overwhelmed or – worse – suckered by those who’d try to persuade you of something that’s not true, cloaked in pseudoscience, that’s abundant and available on-line and, occasionally, in some doctors’ offices.

This week I brushed up on Parkinson’s disease. What drew me into this mini-review is an informative article, “Sergey’s Search,” that appeared in the July (print) issue of Wired and is now available on-line. The feature, by Thomas Goetz, offers insight on what it’s like to know that you’ve got a genetic disposition to Parkinson’s, details on some enzymes implicated in the illness and, further, considers what might be done to help future patients.

I recommend this article to any of my readers who are interested in genetics, Parkinson’s and/or what some even consider as a new era for health-related research.

There’s a lot to take in –

The Wired story starts with Google co-founder Sergey Brin. A Moscow native and, more recently, a California swimmer, Brin’s got his reasons for concern. He’s got a strong family history, for one thing: the illness has affected both his mother and aunt. It turns out Brin has a genetic disposition to develop the condition because he shares the disease-associated G2019S mutation with his mom. As Goetz explains, this alteration in the DNA segment of the gene encoding LRRK2, a leucine-rich repeat kinase, involves a single-nucleotide switch of an adenine for a guanine.

(I’ll add this, just in case you’re interested: the gene encoding LRRK2, or dardarin, resides at human 12q12 – that’s the long arm of chromosome 12. The G2019S nomenclature indicates that the mutation results in a change at the 2019th amino acid position along the protein’s encoded structure, so that a glycine, normally present, is replaced by a serine molecule at that spot. A fascinating tidbit, news to me today, is that when the gene was first cloned in 2004 the researchers, who’d studied several affected families of Basque origin, called it dardarin, derived from the Basque word dardara, meaning tremor.)

The G2019S mutation is relatively common among Ashkenazi Jews. Still, not all of those who carry the mutation develop the disease, and not all who have the disease have this particular mutation. Other genetic variants have been identified, and it’s not clear exactly how these wreak havoc with LRRK2’s function. Enzymes like LRRK2, a kinase, usually transfer ATP molecules from one protein to another. The presumption is that in Parkinson’s, abnormalities in this enzyme’s function – whether they’re caused by this particular mutation or another – somehow lead to loss of dopamine-producing cells in the brain.

Back to Sergey’s story –

“Brin didn’t panic,” Goetz reports (a point I’d emphasize too). Rather, he was reassured by his mother’s experience and high level of functioning with the disease. She still goes skiing (among other things one’s mother might do), he reasons.

What Brin is doing, along the lines of Goetz’s Decision Tree approach, is cutting his risk as best he can. He exercises regularly, doesn’t smoke, and funds research.

Like other rock star informaticists before him (think of Netscape founder James H. Clarke, who launched Healtheon and Steve Case, who started Revolution Health – these are my examples), Brin is struck by the slow pace of medical investigation:

“Generally the pace of medical research is glacial compared to what I’m used to in the Internet,” Brin says. “We could be looking lots of places and collecting lots of information. And if we see a pattern, that could lead somewhere.”

If only medical research could be more like Google…

Some clinical background:

Parkinson’s, a progressive and often debilitating neurological condition, affects a half million or so people in the U.S. As a practicing as a physician, I cared for many patients who had this illness. Although I would see them for other reasons, it was hard not to notice, and know, the characteristic tremor, rigidity and shuffling walk of those affected. The onset of symptoms is usually insidious, slow and unnerving.

As Goetz indicates, most of what doctors understand about Parkinson’s comes from observing patients in the clinic. Illness emerges, it’s thought, as the number of dopamine-producing cells in the brain diminishes. Dopamine is a neurotransmitter, a molecule that transmits messages between cells or groups of cells within the nervous system. Since around 1967, when the drug Levodopa was first marketed, doctors have prescribed this and other pills for people who have Parkinson’s. While these meds can ameliorate symptoms, these don’t reverse the unstoppable deterioration of body and, ultimately, the mind.

One problem with Parkinson’s research and treatment is that once the disease becomes evident, it’s hard – probably too late – to reverse the loss of dopamine-producing cells. Most people don’t develop symptoms until dopamine production is around 20 percent of normal levels. Now, with the advent of genetic markers and potential to “catch” this disease early on, there’s an opportunity for early intervention.

One promising area for Parkinson’s research:

LRRK2 is a kinase, a kind of enzyme that’s over-active in some cancers. Already, pharmaceutical companies have developed specific kinase inhibitors; a dozen or so are already FDA-approved for treatment of particular cancers, and many more are in the pipeline.

What excites me, in all of this, is the possibility that these drugs might be effective in patients with Parkinson’s disease. And because the same enzyme – LRRK2, or dardarin – is implicated in cases without the particular G2019S mutation, it may be that these drugs would work even in cases that lack this particular genetic feature. (There are examples in oncology, in terms of tumor genetics and responsiveness to targeted drugs, that would support this contention, but that’s just theory for now.) The bottom line, as I see it, is that these new drugs should be carefully tested in clinical trials.

Sergey’s view:

One of the key ideas in Goetz’s piece has to do what he considers and may well be a revolutionary approach to medical research.

…Brin is after a different kind of science altogether. Most Parkinson’s research, like much of medical research, relies on the classic scientific method: hypothesis, analysis, peer review, publication. Brin proposes a different approach, one driven by computational muscle and staggeringly large data sets. It’s a method that draws on his algorithmic sensibility—and Google’s storied faith in computing power…

In what may indeed be a “fourth paradigm” of science, as attributed to the late computer scientist Jim Gray, there’s an inevitable evolution away from hypothesis and toward patterns.

As I understand it, Brin seeks to invert the traditional scientific method by applying Google-size data-mining power to massive and very imperfect data sets in health. Already, he and his colleagues have accomplished this by Google’s Flu Trends, which several years ago beat the CDC to an epidemic’s discovery by two weeks.

You should read this article for yourself, as I’m afraid I can’t adequately describe the potential powers of computational health and science analyses that might be applied to well, pretty much everything in medicine. This goes well beyond a new approach to finding a cure for Parkinson’s disease.

This story, largely based in genomics and computational advances, reflects the power of the human mind, how the gifted son of two mathematicians who fell into a particular medical situation, can use his brains, intellectual and financial resources, and creativity, to at least try to make a difference.